US5773578A - Proteins produced by human lymphocytes, DNA sequence encoding these proteins and their pharmaceutical and biological use - Google Patents

Proteins produced by human lymphocytes, DNA sequence encoding these proteins and their pharmaceutical and biological use Download PDF

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US5773578A
US5773578A US08/416,478 US41647895A US5773578A US 5773578 A US5773578 A US 5773578A US 41647895 A US41647895 A US 41647895A US 5773578 A US5773578 A US 5773578A
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lag
protein
sequence
seq
cells
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Thierry Hercend
Frederic Triebel
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Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
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Institut Gustave Roussy (IGR)
Institut National de la Sante et de la Recherche Medicale INSERM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/026—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a baculovirus
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/868—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, or immunotolerance

Definitions

  • the present invention relates to proteins produced by human lymphocytes and, in particular, to a protein expressed at the surface of the latter, DNA sequences coding for these proteins and the pharmaceutical and biological uses of these proteins.
  • IgSF immunoglobulins
  • the immunoglobulins and the T receptors may function as monomorphic ligands critical in cell-cell interactions (for example ICAM, CD4, CD8), receptors for viruses (for example CD4, ICAM) or receptors for the lymphokines (for example IL1-R, IL6-R).
  • monomorphic ligands critical in cell-cell interactions for example ICAM, CD4, CD8
  • receptors for viruses for example CD4, ICAM
  • receptors for the lymphokines for example IL1-R, IL6-R.
  • the inventors have attempted to discover novel genes coding for hitherto undescribed membrane proteins.
  • the present invention relates to a DNA sequence comprising the nucleotide sequence designated FDC, corresponding to the cDNA sequence represented in the sequence SEQ ID No. 1.
  • the present invention also relates to the protein encoded by FDC, namely the protein LAG-3 represented in the sequence ID NO:9 (protein sequence renumbered 1 to 498).
  • the first 28 amino acids should constitute a signal sequence which has been removed in the mature protein.
  • the present invention relates more particularly to the protein corresponding to the protein sequence 1 to 470 of SEQ ID NO.7.
  • the mature protein constitutes a membrane protein of type I of 470 amino acids, the theoretical molecular mass of which deduced from the protein structure is 51295 daltons and the isoelectric point is 10.9. It comprises an extra-cellular region containing about 420 amino acids and a cytoplasmic region containing about 24 amino acids linked by a transmembrane peptide containing about 26 amino acids.
  • the extra-cellular part of the LAG-3 protein corresponds to the amino acids 1 to 420 of the LAG-3 protein described above.
  • the genes of eucaryotic cells exhibit the phenomenon of polytypy. As a result of this phenomenon, some of the amino acids of the coded protein are sometimes replaced without modification of the activity.
  • the present invention includes the proteins resulting from this phenomenon.
  • the present invention relates more generally to a protein having the peptide sequence corresponding to the sequence SEQ ID No. 2, SEQ ID NO:7, SEQ ID NO:9 and the sequences which differ from it by one or more amino acids and which possess the same activity.
  • the present invention also relates to this DNA sequence.
  • the present invention also relates to a DNA sequence comprising the promoter DNA sequence as defined above and a DNA sequence coding for a protein according to the present invention.
  • the inventors first isolated an FDC complementary DNA by means of the following operations.
  • lymphocyte cells known as natural cytotoxic cells
  • RNA preparation of a single-stranded DNA probe from the messenger RNA of the cells and purification by means of a subtraction-hybridization technique so as to select the copies of the RNAs present in the natural cytotoxic lymphocyte cells and absent from other transformed hematopoietic cells.
  • the protein sequence according to the invention was obtained by:
  • the proteins according to the invention may also be obtained by other methods of purification of membrane proteins or by classical peptide synthesis or also by application of genetic engineering techniques comprising the insertion of a DNA sequence coding for a protein according to the invention into an expression vector such as a plasmid and the transformation of cells with this expression vector and the culture of these cells.
  • the present invention also relates to plasmids and expression vectors comprising a DNA sequence coding for a protein according to the invention as well as hosts transformed with this vector.
  • the present invention also relates to a therapeutic composition containing as active ingredient a protein according to the invention or a part of this protein, in particular the soluble part corresponding to the extracellular region of the protein extending from amino acid 1 to amino acid 420 of the protein sequence previously described or a part of this extracellular region and, in particular, all or part of at least one of the four extracellular domains of the immunoglobulin type of the LAG-3 protein (sequences 1 to 142, 143 to 232, 233 to 342 and 343 to 413).
  • the part of the protein may also be constituted by all or part of the cytoplasmic region (sequence 450 to 470).
  • the extracellular part may, in particular, be the sequence represented in the sequence SEQ ID No. 3.
  • This therapeutic composition is active in the treatment of certain diseases implicating the immune system in which the binding of the ligand(s) of the LAG-3 protein to this protein causes the transmission of signals into the interior of the cell, or modifications of cellular interactions.
  • composition according to the invention may act by binding the ligand(s) of the membrane protein LAG-3, thus preventing the detrimental binding of this ligand or these ligands to the LAG-3 protein by a phenomenon of competitive inhibition.
  • the present invention also relates to monoclonal antibodies directed against a protein according to the invention or an immunogenic sequence of such a protein, in particular a peptide sequence comprising the sequence represented in SEQ No. 3.
  • the present invention also relates to hybridomas producing such monoclonal antibodies.
  • the present invention also includes the fragments and derivatives of the monoclonal antibodies according to the invention which react with defined regions of the LAG-3 protein.
  • Such fragments are, in particular, the F(ab') 2 fragments which may be obtained by enzymatic cleavage of the antibody molecules with pepsin, the Fab' fragments which may be obtained by reduction of the disulfide bridges of the F(ab') 2 fragments and the Fab fragments which may be obtained by enzymatic cleavage of the antibody molecules with papain in the presence of a reducing agent.
  • F(ab') 2 fragments which may be obtained by enzymatic cleavage of the antibody molecules with pepsin
  • the Fab' fragments which may be obtained by reduction of the disulfide bridges of the F(ab') 2 fragments
  • the Fab fragments which may be obtained by enzymatic cleavage of the antibody molecules with papain in the presence of a reducing agent.
  • Fv fragments may
  • the monoclonal antibody derivatives are, for example, antibodies or fragments of these antibodies to which markers such as a radioisotope are linked.
  • the monoclonal antibody derivatives are also antibodies of fragments of these antibodies to which therapeutically active molecules, in particular cytotoxic substances, are linked.
  • the monoclonal antibodies or the soluble fractions of the LAG-3 protein and, in particular, all or part of at least one of the four extracellular domains of the immunoglobulin type of the LAG-3 protein (sequences 1 to 142, 143 to 232, 233 to 342 and 342 to 413) or the cytoplasmic region (sequences 450 to 470) of this protein may be used in the treatment of human diseases due to infection by viruses of the HIV type.
  • They may also be used in the treatment of the human diseases caused by viruses binding specifically to the LAG-3 molecule and, in particular, to the first, NH 2 -terminal external domain.
  • the present invention also relates to a dosing or identification method for the proteins according to the invention which comprises the use of the monoclonal antibodies according to the invention.
  • the monoclonal antibodies directed against the proteins according to the invention or fractions of them may be prepared according to a standard method.
  • the protein fractions may be coupled if necessary to an immunogenic agent such as tetanus toxoid by means of a coupling agent such as glutaraldehyde.
  • FIG. 1 presents the restriction map of the FDC cDNA and the clones of cDNA which have enabled the sequence of the FDC clone to be determined;
  • FIG. 2 presents the restriction map and the distribution of exons and introns in the LAG-3 gene
  • FIG. 3 is a schematic representation of the LAG-3 protein
  • FIG. 4 presents a model of the domain 1 of the LAG-3 protein; (corresponding to amino acid residues 1 to 139 of SEQ ID NO:7);
  • FIG. 5 presents the alignment of the domains 1 and 2 (corresponding to amino acid residues 304 to 264 of SEQ ID NO:9) with the domains 3 and 4 (corresponding to amino acid residues 304 to 435 of SEQ ID NO:9) of the LAG-3 protein;
  • FIG. 6 presents the alignment of the peptide sequences of LAG-3 (SEQ ID NO:9) and the CD4 (SEQ ID NO:8) protein of the rat;
  • FIG. 7 presents the result of an immunoprecipitation of membrane proteins of PHA-blasts
  • FIG. 8 is a schema for the preparation of a transfer vector (baculovirus system).
  • FIG. 9 presents the result of the detection by immofluorescence of LAG-3C in the baculovirus system by means of a heteroantiserum
  • FIG. 10 shows by immunofluorescence the reactivity of a heteroantiserum on PHA-blasts and PBL;
  • FIG. 11 presents the result of the detection of LAG-3S in the baculovirus system by means of a heteroantiserum in a Western blot.
  • the mass culture was carried out in the presence of recombinant interleukin-2 and the supernatant of lymphocyte-conditioned medium on a feeder substratum of allogenic irradiated mononucleated blood cells and a cell line transformed by the EBV virus (called LAZ 388) on V-bottomed 96-well plates. 3000 cells were placed in each well at day 0. The pooling of 200 plates with 3 ⁇ 10 6 cells per ml at day 12 gave a harvest of 6 ⁇ 10 9 cells.
  • the preparation of the cytoplasmic RNAs, the RNAs bound to the membranes of the endoplasmic reticulum and the mRNAs was performed by introducing some modifications to the methods described by Maniatis (2), Mechler (3) and Aviv (4).
  • 4 ⁇ 10 9 F55IIIE5 cells were loaded onto sucrose gradients after hypotonic shock and mechanical grinding according to the method described by Mechler.
  • the cytoplasmic RNAs borne by the ribosomes bound to the membranes of the endoplasmic reticulum were purified between sucrose gradients.
  • RNA of the so-called MB membrane-bound
  • the methods of purification described by Aviv (4), Maniatis (2) and Triebel (5) made possible the isolation of RNAs of the various clones and cell lines which are used and mRNAs of Jurkat, U937, Laz388 and K562 cells (about 10 9 cells of each line) which are used to subtract the probe.
  • lysis buffer 50 mM Tris HCl, 62.5 mM EDTA, 0.4% Triton X-100 surfactant, 2.5M LiCl
  • lysis buffer 50 mM Tris HCl, 62.5 mM EDTA, 0.4% Triton X-100 surfactant, 2.5M LiCl
  • the lysis buffer is transferred to cold EPPENDORF tubes containing 50 ⁇ l of 10% NP40.
  • RNA is removed and introduced into FALCON tubes containing 1 ml of phenol, 1 ml of CHCl 3 , 1 ml of STE 2% SDS (150 mM NaCl, 10 mM Tris, 1 mM MgCl 2 , 2% SDS).
  • the tubes are centrifuged for 10 min. at 5000 rev/min.
  • the upper phase is removed, 1 ml of phenol and 1 ml of chloroform are added. After centrifugation for 5 min. at 5000 rev/min., the upper phase is removed.
  • the cells are taken up in ice-cold hypotonic RSB buffer (10 mM KCl, 1.5 mM MgCl 2 , 10 mM Tris-HCl, pH 7.4) treated beforehand with 0.1% DEPC at 10 8 cells/ml. They are left on ice for 5 min. The cells are ruptured mechanically by means of 10 strokes of a DOUNCE homogenizer (type B). The homogenate is centrifuged at 1000 g for 2 min in order to sediment the nuclei. The supernatant or "cytoplasmic extract” is then used for the separation of free ribosomes/membrane extracts.
  • DOUNCE homogenizer type B
  • cytoplasmic extract 0.7 ml of cytoplasmic extract is mixed with 3.2 ml of 2.5M sucrose TK buffer (0.05M Tris-HCl, pH 7.4, 0.15M KCl, 0.005M MgCl 2 ), then this mixture is layered onto 2 ml of 2.5M sucrose TK. 8 ml of 2.05M sucrose TK are added, followed by 4 ml of 1.3M sucrose TK.
  • the gradients are centrifuged at 4° C. for 5 h in a swinging rotor of the SPINCO SW28 type at 25000 rev/min.
  • the tubes are punctured with a needle at the interphase between the 2.05M and the 1.3M sucrose gradients.
  • TE 10:1 10 mM Tris HCl, 1 mM EDTA
  • An extraction is made with phenol, then with a phenol-chloroform mixture.
  • Precipitation is effected with 1/10 of 3M NaAc and 2.5 vol. of ethanol.
  • RNA is dissolved in water and heated at 65° C. for 5 min. An identical volume of loading buffer is added twice. The temperature is allowed to equilibrate. The effluent is collected. It is heated at 65° C. and the sequence is repeated.
  • loading buffer 20 mM Tris-HCl (pH 7.6), 0.5M NaCl, 1 mM EDTA supplemented with SDS.
  • the column is washed with H 2 O, a 0.1M NaOH solution and 5 mM EDTA and water. It is then washed with 5 volumes of loading buffer.
  • the RNA is dissolved in water and heated at 65° C. for 5 min. An identical volume of loading buffer is added twice. The temperature is allowed to equilibrate. The effluent is collected. It is heated at 65° C. and the sequence is repeated.
  • the column is washed with 5 to 10 volumes of loading buffer, then with 4 volumes of loading buffer-0.1M NaCl.
  • the poly(A) + is eluted with 2-3 volumes of 10 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.05% SDS. 3M sodium acetate (pH 5.2) is added at 1/10. Precipitation is effected with 2.2 vol. of ethanol.
  • the double-stranded cDNAs were cloned into the EcoRI site of the phage Lambda gt10 with the aid of the EcoRI linker.
  • the preparation of the single-stranded complementary DNA probe is carried out by subtraction by means of two cycles of hybridization on an excess of messenger RNA of the cells said "to be eliminated" (Jurkat, Laz 388, U937, K562), followed by passage through hydroxyapatite columns which enables the double-stranded cDNA-mRNA complex to be separated. After 2 hybridization cycles and 2 passages through the column about 6-7% of the radioactivity remain, i.e. that about 7% of the F55IIIE5 material called MB ("membrane-bound") does not exist in the Jurkat, K562, U937 and Laz 388 cells. It is this material which serves as probe for the detection of the corresponding cDNAs in the MB-F55IIIE5 library.
  • This technique makes use of the subtraction-hybridization conditions described by Davis et al (7).
  • a single-stranded cDNA probe is prepared labelled with 32 P-dCTP (specific activity: 800 Ci/mmol -1 ) in a volume of 50 ⁇ l.
  • the mixture is left for 1 h at -20° C. before being centrifuged, washed with 70% ethanol and dried.
  • the precipitate is taken up in 7.5 ⁇ l of H 2 O, and 7.5 ⁇ l of 0.5M NaH 2 PO 4 , pH 7, 1mM EDTA, 0.25% SDS are added.
  • the solution is incubated in the incubator at 68° C. for 20 hours.
  • the solution is diluted with 1 ml of 0.12M NaH 2 PO 4 , 0.1% SDS. It is loaded onto a hydroxyapatite column equilibrated with the same buffer at 60° C.
  • the effluent (single-stranded material) is concentrated using 2-butanol and passed through a G-50 column in order to remove the phosphate buffer. 7 ⁇ g of mRNA of each of the lines are added again and the hybridization and passage through the column are repeated. After these 2 passages, 7% of the starting amount of radioactivity are recovered.
  • the previously constructed cDNA library (2 ⁇ 10 4 recombinant phages) is inoculated into E. coli C600/Hf1.
  • the screening is performed in accordance with the usual techniques using nylon filters as described by Huynh (8).
  • Hybridization with the probe previously obtained is carried out at 42° C. with prehybridization with a hybridization solution of the Southern type and addition of 5 ⁇ 10 6 cpm/ml of the single-stranded MB-F55IIIE5 subtracted probe.
  • the plating of the positive phages, the purification of the corresponding DNAs, the purification of the complementary DNAs in the form of fragments by excision from an agarose electrophoresis gel with a low gelling point were carried out according to the method described by Maniatis (2) and Huynh (8).
  • the ligation of the longest cDNAs in the plasmid vector pBS digested by the EcoRI endonuclease and treated with the alkaline phosphatase calf intestine, the transformation of competent JM 109 bacteria and the screening of the recombinants by a double selection system (ampicillin+X-gal/IPTG) were carried out according to the methods of genetic engineering conventionally used.
  • the purification and the preparation on a large scale of the recombinant complementary DNAs cloned in pBS were carried out by using the method of purification on a cesium chloride gradient described by Mianiatis (2).
  • a cDNA clone was isolated which has been designated FD47 and which consists of 400 bp and hybridizes with the probe obtained by subtraction-hybridization. This clone was selected, on the one hand, because it hybridizes with a transcript of 2 kb constantly found in the F55IIIE5 cells but not in the Jurkat, Laz 388, K 562 and U 937 cells in the "Northern blot” techniques and, on the other, because it shows no homology with any of the known sequences of the data bank entitled "Genebank”.
  • the FD47 clone contains a nucleotide region capable of coding for a hydrophobic transmembrane region.
  • RNA probe labelled with 32 p is constructed starting from FD47 by in vitro transcription from the pBS plasmid using the T7 polymerase in the presence of 32 P-UTP (800 Ci.mmole -1 ) according to the method described by Triebel (5).
  • the three libraries are constructed from the messenger RNA derived from CD3 + clones bearing the ⁇ and ⁇ of the T receptor and which transcribe a LAG-3 message in considerable quantities when their RNA is tested with the FD47 probe.
  • the FD47 probe is used to screen the first cDNA library in order to obtain the clone FD19.
  • a 0.3 kb Bam HI - Hind III genomic fragment comprising the most 5' part of the IV exon is labelled using as primer a random hexamer and it is used to screen the second library to obtain the clones FD61 and FD101, and the third library in order to obtain a cDNA containing the almost full-length 5' end, called FD191.
  • sequences of the clones FD47 and FD19 were determined directly in the pBS vector by the method of Sanger (9) using a universal M13 primer or a reverse 113 primer and the modified T7 polymerase.
  • the sequences of FD61, FD101 and FD191 were determined front single-stranded DNA after cloning in the vector M13mp18.
  • FDC sequence The set of the total nucleotide sequences of these cDNAs called "FDC sequence" consisting of 1871 bp indicates that the messenger RNA of the LAG-3 gene has a long and open reading frame and codes for a protein of 498 amino acids, the peptide sequence of which is obtained by deduction from the nucleotide sequence of the cDNA.
  • the FDC cDNA itself was obtained by ligation of the 2 complementary FcoRI-HindIII fragments, one covering the 5' part of the FD191 clone, the other covering the 3' part of the FD19 clone, thus producing a clone covering the entire known sequence, as illustrated in FIG. 1.
  • Genomic DNA clones are isolated from the LY67 library made from DNA of a human B cell line transformed by EBV, partially digested with Mbo-I and inserted into the phage lambda 2001 as described by Dariavach (10).
  • the FD47 insertion segment is labelled by means of the hexamer random priming method described by Feinberg (11) and used to screen 2 ⁇ 10 5 plaques of the human genomic DNA library.
  • Nine positive plaques (GD1 to GD9) are isolated and the phage DNAs are characterized by restriction mapping using the FD19 probe containing half of the region coding for the protein and the untranslated 3' region.
  • sequences of these fragments are determined from single-stranded DNA using the dideoxy chain termination procedure described. Oligonucleotides containing 17 bases, the sequences of which are obtained either from the cDNA of FD19 or from the sequence of the 5' flanking region of the LAG-3 gene are synthesized and used for sequencing.
  • FIG. 2 illustrates the exon-intron organisation of the human LAG-3 gene.
  • the map was constructed after single and double digestion by endonucleases of the GD 2 and GD 3 clones obtained from lambda 2001 and their subclones GD 3 Eco and GD 1 Hind. The untranslated regions are represented by a fine line.
  • the LAG-3 gene spans approximately 6.6 kb and is divided into 8 exons, the first nucleotides of which are located at positions 1, 289, 437, 742, 1012, 1288, 1531 and 1662 of the DNA sequence previously described.
  • the nucleotide sequence contains a CCAAT box in reverse (i.e. ATTGG) at position -662 from the ATG sequence signalling the initiation of translation.
  • the CCAAT box is known to be crucial in many promoters and may function in the reverse orientation.
  • an Sp1 binding site containing the typical GGGCGG core hexanucleotide is also located at position -389 from the translation initiation site.
  • the DNA of the K562 tumor cell line and of the polyclonal IL-2-dependent T and NK cell lines are digested with EcoRI, Hind III, Bam HI or XbaI.
  • Southern Blot hybridizations are performed using the FDC probe (1871 bp), constructed by fusion of the 5' EcoRI/Hind III fragment of the FD191 clone with the 3' Hind III/EcoRI fragment of the FD19 clone.
  • 3 fragments of 2, 8.2 and 10 kb are obtained with EcoRI, 2 fragments of 5.7 and 9.5 kb with Hind III, 3 fragments of 2.8, 4 and 13 kb with Bam HI and 3 fragments of 3, 4 and 6 kb with XbaI.
  • the 1004 bp fragment inserted in the FD19 clone was used as probe to analyse the cellular distribution of the expression and the regulation of the expression of the LAG-3 gene.
  • RNA "blotting" clearly show that the subtraction-hybridization procedures used in the first screening of the F55IIIE5 sub-library were performed successfully with respect to the isolation of the FD19 clone of the cDNA library in the sense that no LAG-3 transcript is expressed in the transformed cell lines of T, B and myeloid origin (in particular Jurkat, Laz 388, K 562, U 937).
  • messenger RNA was not detected in fresh, purified T cells nor in peripheral macrophages nor in resting lymphocytes, within the limits of detection usually accepted for this technique.
  • LAG-3 gene has also been studied in the nervous tissues of neuroectodermal origin and no messenger RNA was detected in either the neuroblastoma cell lines in culture or in fresh cerebral tissue.
  • the LAG-3 gene is only expressed in the T and NK cells after activation.
  • the expression of the LAG-3 gene is maximal 3 to 4 days after activation of the blood lymphocytes by phytohemagglutinin.
  • the protein corresponds to what is appropriately called an activation antigen.
  • LAG-3 protein shown in FIGS. 3, 4 and 6, have been deduced from the structure of the gene and from the analysis of its translation product. It appears to be a type I membrane protein containing 498 amino acids.
  • the domains are designated by L (leader domain), V (V domain of the immunoglobulin type), C 2 (C 2 domain of the immunoglobulin type) (19), TM (transmembrane) and CYT (cytoplasmic).
  • L leader domain
  • V V domain of the immunoglobulin type
  • C 2 C 2 domain of the immunoglobulin type
  • TM transmembrane
  • CYT cytoplasmic
  • the position of the introns is indicated by arrows.
  • the N-glycosylation sites 31 and the RGD sequence 32 (cell attachment sites) are also indicated.
  • the mature protein comprises 470 amino acids with a theoretical molecular mass of 51295 daltons and an isoelectric point of 10.9 based on protein structure analysis. It contains a leader peptide L (28 amino acids) encoded by the exons I (19 amino acids) and II (9 amino acids out of 50). The extracellular region is encoded by the exons II (41 amino acids out of 50), III (101 amino acids), IV (90 amino acids), V (92 amino acids) and VI (81 amino acids), the transmembrane (TM) region by the exon VII (44 amino acids) and the cytoplasmic region including strongly charged amino acids by the exon VIII (21 amino acids). The extracellular region contains 8 cysteine residues and 4 potential N-glycosylation sites (Asn-X-Ser, Thr).
  • FIG. 4 presents a model of domain 1 of the LAG-3 protein.
  • the sequence of the first domain of the Ig type (amino acids +1 to +139) is represented according to the model used by Amzel and Poljak (12). The disulfide bridge is shown and the RGD sequence is boxed in.
  • the peptide segment encoded by the exons II and III corresponds to a V type IgSF domain as described by Williams (13) including the ⁇ -strands A, B, C, C', C", D, E, F and G shown in FIG. 6, possessing two unusual features.
  • this V-type domain includes an extra loop of approximately 30 amino acids encoded by the first part of the exon III.
  • This loop shown in FIG. 4 joins the ⁇ -strand C to the ⁇ -strand C' and contains, in particular, ten proline residues. It seems that such an insertion might be compatible with a IgSF-type fold to the extent that it does not cause rupture of the central core of the fold that is considered to consist of the ⁇ -strands A, B, E and G, F, C as described by Lesk (14).
  • This extra loop acts as immunogen since it is probably exposed at the outside of the molecule and consequently is exposed to recognition by antibodies.
  • V-type and C-type domains appear in the middle of the Ig-type fold at this site, i.e. in the region of the C ⁇ -strand.
  • the second unusual feature is that the cysteine downstream from domain 1 seems to be located in the ⁇ -strand G rather than in the ⁇ -strand F (residue 121), as is almost invariably the case.
  • the sequence Asp-Gly-Tyr-Cys (SEQ ID NO:10) is located very characteristically in the ⁇ -strand F and is found here, except that an Ala residue replaces the Cys residue (FIG. 4). It seems possible that a disulfide bridge may be formed and, for example, it should be noted that an unusual disulfide bridge of a different kind has been devisved in the V-type domain of the ⁇ chain of CD8 as described by Kirszbaum (16).
  • Arg-Gly-Asp (RGD) sequence is found in the ⁇ -strand E (FIG. 4). This sequence is known to represent a potential adhesiotope as described by Ruoslahti (17) but it has not been established whether it forms the core of an essential binding site since, in this position, such a sequence would probably be located within the IgSF-type fold.
  • the domains 1 and 2 of LAG-3 were aligned and compared by eye with the domains 3 and 4, taking into account identities and structural considerations.
  • FIG. 5 shows the internal homology of LAG-3.
  • domain 1 The amino acid sequences of domain 1 (starting from position 91 in FIG. 5 (and in accordance with the numbering in FIG. 5) after the extra loop) and domain 2 were aligned with the corresponding positions in domains 3 and 4.
  • the identities are indicated by (*) and the similarities by (.).
  • domain 1 contains a sequence forming an extra loop
  • the alignment was begun at amino acid 91 in this domain and at amino acid 276 in domain 3 of FIG. 5.
  • Out of 129 possible matches between residues, 34 identities, 35 similarities and 9 breaks were observed (alignment score greater than +8.5 SD).
  • WxC sequence which is most unusual at this position where the sequence Y or FxC is usually found, as described by Williams (13).
  • the sequences of LAG-3 and CD4 of the rat have also been aligned, as is shown in FIG. 6.
  • the dotted lines above the sequences show the positions of the ⁇ -strands in the four IgSF-type domains.
  • the leader sequence L and the transmembrane sequence (TM) are shown by a continuous line above the sequence.
  • the position of the introns is shown by arrows above the sequence (for LAG-3) and below the sequence (for CD4) as described by Maddon (20) for human CD4.
  • Two large gaps are inserted corresponding to the sequence of the extra loop in domain 1 of LAG-3 and in order to account for the fact that domain 3 of CD4 is a V-type domain, whereas domain V of LAG-3 is a C2-type domain.
  • the fragments of similarity comprise the start of domain 1 (9 identities and 10 similarities out of 17 possible matches), and the very unusual sequence WxC in domains 2 and 4 of LAG-3, which are also present at the corresponding positions in CD4. This sequence pattern is not found in an equivalent position in any other IgSF-type domain.
  • One of the principal features of LAG-3 is, consequently, its relationship to CD4.
  • LAG-3 As in the LAG-3 structure known fragments having internal sequence homologies have been found in the CD4 molecule between domains 1 and 3 as well as between domains 2 and 4. More generally, the exon/intron organisation of LAG-3 and CD4 is very similar: both genes comprise an intron within the first IgSF-type domain and the position of the introns (shown by arrows in FIG. 6) in LAG-3 is very similar to that of CD4.
  • CD4 has evolved by gene duplication from a pre-existing structure with 2 IgSF-type domains.
  • the present discovery strengthens this hypothesis and the inventors suggest, on the basis of similarities of sequence and exon/intron organisation, that CD4 and LAG-3 have thus shared a common 4-domain ancestor.
  • the LAG-3 protein may thus be expected to function as do many other molecules of the superfamily of the Ig type as ligand for a soluble protein or for a membrane protein.
  • the known examples include proteins whose expression is positively regulated by cell activation such as ICAM-1, known to be involved in cell-cell interactions, or IL1-R and IL6-R which function as receptors for growth factors.
  • LAG-3 protein is expressed in substantial amounts on activated lymphocytes (probably more than 5000 sites per cell given the limits of detection of indirect techniques of immunofluorescence with a rabbit anti-serum in flow cytometry) and taking into account its homology with CD4, the very likely function of LAG-3 is one of intercellular adhesion.
  • the characterization of the receptor-ligand couples (for example ICAM-1/LFA-1 or CD4/MHC, class II) in this domain is in progress.
  • the CD4 molecule has been crystallized and its atomic structure deduced by X-ray analysis (Ryu (22) Wang (23)).
  • ICAM-1 the first NH 2 -terminal domain (domain 1) contains binding sites for LFA-1 and attachment sites for the rhinoviruses (Staunton (25)).
  • domain 1 contains binding sites for LFA-1 and attachment sites for the rhinoviruses (Staunton (25)).
  • Staunton (25) Two therapeutic applications which follow from knowledge of the structure of ICAM-1 have been described.
  • the expression of ICAM-1 is considerably enhanced at the surface of the bronchial epithelium during asthmatic disease and in a model of a cynomolgus monkey made asthmatic, it is possible to reduce the infiltration of the bronchi by eosinophil granulocytes and to improve the clinical state by intravenous injection of anti-ICAM antibodies (Wegner (26)).
  • the soluble ICAM-1 molecule inhibits the infection of human cells by rhinoviruses by blocking the attachment of the virus to the natural ICAM-1 molecule at the surface of the cells by competition (Marlin (27)).
  • LAG-3 may be a site of entry for a virus.
  • one of the possible attachment sites may consist (by analogy with CD4) in this case of all or part of the following amino acid sequence including, in particular, the ⁇ -strand C" of domain V: Gly Leu Arg Ser Gly Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu Arg (corresponding to the amino acids 80 to 97 of the LAG-3 protein, SEQ ID NO:7).
  • the LAG-3 gene has been localized on chromosome 12 (band p 13.3) (Triebel (28)) close to CD4.
  • Anti-LAG-3 rabbit antibodies were obtained after repeated injections of a synthetic peptide coupled to KLH into rabbits.
  • This peptide comprises 30 amino acids forming the sequence shown in the sequence SEQ ID No3 included in the extra loop of domain V of LAG-3.
  • the LAG-3 protein does exist in the form of a single chain, probably glycosylated, at the surface of the T cells.
  • This estimated molecular mass is very similar to the theoretical molecular mass of 54457 corresponding to the 498 amino acids of the LAG-3 polypeptide with an intact, uncleaved signal peptide. No translation product larger than 20,000 daltons could be detected using the anti-sense LAG-3 RNA as substrate in the reaction with the rabbit reticulocyte extract.
  • This system was described by Luckow (21) after transfection of the recombinant plasmid and the viral genome; the SF9 cells are selected by successive purifications (screening of recombinants), thus making possible the production of considerable amounts of recombinant protein.
  • This protein is normally cleaved (the hydrophobic signal peptide is removed inside the cell) and glycosylated (at least partially).
  • the vector PVL941 (obtainable from Dr. Max SUMMERS, University of Texas, U.S.A.) was cut by the restriction enzyme BamHI, then dephosphorylated by calf intestine phosphatase. This was done in order to prevent the autoligation of the vector with itself.
  • a double-stranded oligonucleotide "linker" containing a BglII restriction site was then attached to the Eco47III BglII FDC fragment in order to create the construction LAG 3-C (C for complete) and a linker containing a BamHI site was attached in order to create the construction LAG 3-S (S for soluble).
  • digestion was performed with an excess of restriction enzyme of the BglII type (in the case of the construction LAG 3-C) or of the BamHI type (in the case of the construction LAG 3-S), then the fragments corresponding to the 2 constructions were purified by gel electrophoresis.
  • the last step consisted of linking the BglII LAG 3-C fragment or the BamHI LAG 3-S fragment to the vector PVL 941-BamHI.
  • Competent JM109 bacteria were transformed with the recombinant transfer vector containing one or other of the constructions. Colonies resistant to ampicillin were placed in culture, then the plasmid DNA contained in these bacteria was purified; in this way, a number of clones containing the transfer vector was obtained and clones containing the LAG 3-C fragment or the LAG 3-S fragment in the right orientation were selected.
  • the clone of bacteria thus obtained was placed in culture in 500 ml of medium with ampicillin, then the plasmid was purified on a cesium chloride gradient.
  • the positive wells are located and the wells corresponding to the highest dilutions are retained.
  • This screening technique is performed a second and third time. During the third screening, a check is made that the dots giving a positive signal in "dot blot" hybridization do not contain SF9 cells containing inclusions. These inclusions correspond to the secretion of the protein polyhedrin, produced after infection of SF9 cells by a non-recombined, wild-type virus. This last point was also checked not by direct reading of the plaque but by a procedure involving collection of the cells, spreading them on a glass slide and staining with May-Grunwald-Giemsa.
  • SF9 cells infected with the recombinant viral clone containing the LAG 3-C fragment were obtained on the 5th day of culture after an infection at 0.1 pfu/cell. These SF9 cells express the recombinant LAG-3 molecule at the surface as is shown by the immunofluorescent reactivity of the specific rabbit antibody, compared with the reactivity obtained with uninfected SF9 cells or SF9 cells infected with a AcNPV wild-type virus (FIG. 9). Furthermore, the reactivity of the LAG-3-specific rabbit serum towards the SF9 cells expressing LAG-3 was compared with the reactivity obtained towards T lymphocytes activated by phytohemagglutinin (PHA-blasts).
  • PHA-blasts phytohemagglutinin
  • the histograms obtained are similar and thus show that the number of recombinant LAG-3 molecules (FIG. 9) expressed at the surface of the SF9 cells is comparable to the number of natural LAG-3 molecules expressed at the surface of the activated lymphocytes (FIG. 10).
  • This molecular mass corresponds well with the mass expected of the LAG 3-S Eco47 III-BamHI fusion protein (38038 K daltons) after glycosylation in the SF9 cells.
  • the structure of the part coding for LAG 3-S shows that the first three domains of LAG-3 (upstream from the internal BamHI site) were fused with a nucleotide segment of 56 base pairs of the gene for polyhedrin downstream from the BamHI site.
  • the fusion protein comprises 352 amino acids, 335 corresponding to LAG-3 and 17 being derived from one of the reading frames of the gene for polyhedrin.

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